This invention relates to novel amphiphilic compounds with cleavable hydrophilic headgroups and their use in liposomes. More particularly, the invention relates to novel lipid compounds with hydrophilic headgroups linked to the molecule through a vinyl ether linkage, and their use in liposome vesicle formation and the triggered release of the liposomal contents or triggered permeabilization of, or fusion with, target lipid membranes. In another aspect, the invention also relates to triggered cleavage of the headgroups of novel vinyl ether lipid compounds while incorporated in liposomes, to facilitate a phase transition of the liposome to effect the release of liposomal contents and/or the permeabilization of, and/or fusion with, cellular membranes by the liposomes.
Liposomes have been used as drug delivery vehicles with both passive and active-targeting schemes to attempt to site-specifically deliver the contents of the liposome to target tissues in vivo as well as in cell and tissue culture applications. A significant drawback of previous methods of liposomal delivery systems has been constructing liposomes that have sufficient cell culture or in vivo stability to reach desired tissue sites and/or intra-cellular compartments, but will then efficiently release their contents once at the target site.
A wide variety of liposomal release mechanisms activated by light, heat, low pH, or enzymatic activity have been reported and reviewed. See Gerasimov, O. V., Rui, Y., and Thompson, D. H., Triggered Release from Liposomes Mediated by Physically and Chemically Induced Phase Transitions, Vesicles, Morton Rosoff, ed., Marcel Dekker, Inc., New York, 1996. One such method described in U.S. Pat. No. 5,277,913 provides for triggered phase changes in liposomes containing plasmalogen or plasmalogen analogs to cause release of the liposomal contents. In that disclosure, the vinyl ether linkage bonding one or both of the hydrophobic tailgroups of the lipids forming the liposome is cleaved by low pH conditions or by oxidation mediated by photoactive sensitizer agents. The cleavage results in one or both of the hydrophobic tailgroups dissociating from the molecule, which causes local changes in the liposome structure leading to leaking of liposomal contents or to fusing of the liposome with adjacent membranes. However, these lipids, with labile vinyl ether linkages joining the hydrophobic tail groups to the remainder of the molecule, have limited sensitivity to desirable triggering conditions, as exhibited by slow liposomal content release rates and/or slow membrane fusion kinetics, to be optimal for many applications. One theory for this is that the labile vinyl ether linkage may distribute in the hydrophobic region of lipid bilayers, where access to protons and oxidative agents is limited.
In that no liposome structure has been found to date that is optimal for all applications, there is a need for new liposome compositions which remain stable in vivo and cell culture until they reach their desired target tissues or cellular compartments, whereupon they may be efficiently triggered to release their contents and/or to permeabilize or fuse with target membranes to deliver the liposomal contents into desired sites. It has been surprisingly found that the vinyl ether lipids of the present invention, having cleavable hydrophilic headgroups, facilitate liposome vesicle formation, and when cleaved under specific conditions at desirable target sites, facilitate liposomal content release and/or permeabilization of or fusion with target membranes.